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ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer

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Title: ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer
Authors: Hashimoto, Shigeru Browse this author
Furukawa, Shotaro Browse this author
Hashimoto, Ari Browse this author →KAKEN DB
Tsutaho, Akio Browse this author
Fukao, Akira Browse this author →KAKEN DB
Sakamura, Yurika Browse this author
Parajuli, Gyanu Browse this author
Onodera, Yasuhito Browse this author →KAKEN DB
Otsuka, Yutaro Browse this author
Handa, Haruka Browse this author
Oikawa, Tsukasa Browse this author →KAKEN DB
Hata, Soichiro Browse this author
Nishikawa, Yoshihiro Browse this author →KAKEN DB
Mizukami, Yusuke Browse this author →KAKEN DB
Kodama, Yuzo Browse this author
Murakami, Masaaki Browse this author →KAKEN DB
Fujiwara, Toshinobu Browse this author →KAKEN DB
Hirano, Satoshi Browse this author →KAKEN DB
Sabe, Hisataka Browse this author →KAKEN DB
Keywords: ARF6
mRNA translation
pancreatic driver oncogenes
PD-L1
mevalonate pathway
Issue Date: 27-Aug-2019
Publisher: National Academy of Sciences.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America (PNAS)
Volume: 116
Issue: 35
Start Page: 17450
End Page: 17459
Publisher DOI: 10.1073/pnas.1901765116
PMID: 31399545
Abstract: Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5'-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5'-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor beta (PDGFR beta) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, elF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among elF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.
Rights: https://creativecommons.org/licenses/by-nc-nd/4.0/
Type: article
URI: http://hdl.handle.net/2115/75628
Appears in Collections:国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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